Methods and Apparatus to Increase Secretion of Endogenous Naturetic Hormones

ABSTRACT

A method and apparatus for treatment of heart failure by increasing secretion of endogenous naturetic hormones ANP and BNP such as by stimulation of the heart atria. Heart pacing is done at an atrial contraction rate that is increased and can be higher than the ventricular contraction rate. Pacing may include mechanical distension of the right atrial appendage. An implantable device is used to periodically cyclically stretch the walls of the appendage with an implanted balloon.

This application is a continuation of U.S. application Ser. No.13/426,068, filed Mar. 21, 2012 (U.S. Patent Publication No. US2012/0215272, published Aug. 23, 2012), which is a continuation of U.S.application Ser. No. 11/276,461, filed Mar. 1, 2006, now U.S. Pat. No.8,165,674, issued Apr. 24, 2012, which claims the benefit of U.S.Provisional Application No. 60/657,389, filed Mar. 2, 2005 and U.S.Provisional Application No. 60/678,220, filed May 6, 2005, all of whichare herein incorporated by reference in their entirety.

BACKGROUND

The present invention generally relates to implantable devices forcardiac stimulation and pacing therapy, and more particularly, thepresent invention is concerned with cardiac therapies involving thecontrolled delivery of electrical or mechanical stimulations to theheart for the treatment of congestive heart failure, and an apparatusfor delivering such therapies with the objective of altering secretionof hormones by the heart muscle.

Congestive Heart Failure

Congestive heart failure (CHF) occurs when muscle cells in the heart dieor no longer function properly, causing the heart to lose its ability topump enough blood through the body. Heart failure usually developsgradually, over many years, as the heart becomes less and lessefficient. It can be mild, scarcely affecting an individual's life, orsevere, making even simple activities difficult.

Congestive heart failure (CHF) accounts for over 1 million hospitaladmissions yearly in the United States (U.S.) and is associated with a5-year mortality rate of 40%-50%. In the U.S., CHF is currently the mostcostly cardiovascular disease, with the total estimated direct andindirect costs approaching $56 billion in 1999.

Recent advances in the treatment of CHF with medications, includingangiotensin-converting enzyme (ACE) inhibitors, beta-blockers(Carvedilol, Bisoprolol, Metoprolol), Hydralazine with nitrates, andSpironolactone have resulted in significantly improved survival rates.Although many medications have been clinically beneficial, they fallshort of clinician's expectations and as a result consideration hasturned to procedures and devices as additional and more potent heartfailure therapy.

There has been recent enthusiasm for biventricular pacing (pacing bothpumping chambers of the heart) in congestive heart failure patients. Itis estimated that 30% to 50% of patients with CHF have inter-ventricularconduction defects. These conduction abnormalities lead to adiscoordinated contraction of the left and right ventricles of analready failing and inefficient heart. When the right ventricle alone ispaced with a pacemaker, the delayed activation of the left ventricle,can also lead to significant dyssynchrony (delay) in left ventricularcontraction and relaxation.

Because ventricular arrhythmias continue to threaten CHF patients andmany anti-arrhythmic drugs have unacceptable side effects, asophisticated implantable cardioverter-defibrillator (ICD) device hasshown encouraging results. Biventricular pacing in combination with ICDsdemonstrates a trend toward improved survival. Preliminary data inanimals and humans using subthreshold (of the type that does not byitself cause heart muscle to contract) stimulation of the heart muscleto modulate cardiac contractility are encouraging and may furtherenhance the quality of life of CHF patients.

It is also clear that many patients with CHF are not candidates forbiventricular pacing or do not respond to this treatment strategy. Thisalso applies to other recent advances and experimental therapies. Thereis a clear need for new, better therapies that will improve and prolonglife of heart failure patients and reduce the burden on the medicalsystem. It is particularly important that these new therapies should notrequire a major surgery, prolonged stay in the hospital or frequentvisits to the doctor's office.

Electric Activity of the Heart

In a given cardiac cycle (corresponding to one “beat” of the heart), thetwo atria contract, forcing the blood therein into the ventricles. Ashort time later, the two ventricles contract, forcing the blood thereinto the lungs (from the right ventricle) or through the body (from theleft ventricle). Meanwhile, blood from the body fills the right atriumand blood from the lungs fills the left atrium, waiting for the nextcycle to begin. A healthy adult human heart may beat at a rate of 60-80beats per minute (bpm) while at rest, and may increase its rate to140-180 bpm when the adult is engaging in strenuous physical exercise,or undergoing other physiologic stress.

The healthy heart controls its rhythm from its sinoatrial (SA) node,located in the upper portion of the right atrium. The SA node generatesan electrical impulse at a rate commonly referred to as the “sinus” or“intrinsic” rate. This impulse is delivered to the atrial tissue whenthe atria are to contract and, after a suitable delay (on the order of140-220 milliseconds), propagates to the ventricular tissue when theventricles are to contract. SA node is the natural pacemaker of theheart. If it is disabled, there are other specialized areas of the heartmuscle that can generate an intrinsic heart rate.

The ventricular muscle tissue is much more massive than the atrialmuscle tissue. The atrial muscle tissue need only produce a contractionsufficient to move the blood a very short distance from the respectiveatrium to its corresponding ventricle. The ventricular muscle tissue, onthe other hand, must produce a contraction sufficient to push the bloodthrough the complete circulatory system of the entire body. Even thoughtotal loss of atrial contraction can lead to a small reduction ofcardiac output it is not an immediate risk to life.

Electronic Cardiac Pacemakers

It is the function of a electronic pacemaker (pacemaker) to provideelectrical stimulation pulses to the appropriate chamber(s) of the heart(atrium, ventricle, or both) in the event the heart is unable to beat onits own (i.e., in the event either the SA node fails to generate its ownnatural stimulation pulses at an appropriate sinus rate, or in the eventsuch natural stimulation pulses do not effectively propagate to theappropriate cardiac tissue). Most modern pacemakers accomplish thisfunction by operating in a “demand” mode where stimulation pulses fromthe pacemaker are provided to the heart only when it is not beating onits own, as sensed by monitoring the appropriate chamber of the heartfor the occurrence of a P-wave or an R-wave. If a P-wave or an R-wave isnot sensed within a prescribed period of time (which period of time isoften referred to as the “escape interval”), then a stimulation pulse isgenerated at the conclusion of this prescribed period of time anddelivered to the appropriate heart chamber via a pacemaker lead.Pacemaker leads are isolated wires equipped with sensing and stimulatingelectrodes.

Modern programmable pacemakers are generally of two types: (1)single-chamber pacemakers, and (2) dual-chamber pacemakers. In asingle-chamber pacemaker, the pacemaker provides stimulation pulses to,and senses cardiac activity within, a single-chamber of the heart (e.g.,either the right ventricle or the right atrium). In a dual-chamberpacemaker, the pacemaker provides stimulation pulses to, and sensescardiac activity within, two chambers of the heart (e.g., both the rightatrium and the right ventricle). The left atrium and left ventricle canalso be paced, provided that suitable electrical contacts are madetherewith.

Much has been written and described about the various types ofpacemakers and the advantages and disadvantages of each. For example,U.S. Pat. No. 4,712,555 of Thornander et al. and U.S. Pat. No. 5,601,613of Florio et al. present background information about pacemakers and themanner in which they interface with a patient's heart. These patents arehereby incorporated by reference in their entirety.

One of the most versatile programmable pacemakers available today is theDDDR pacemaker. This pacemaker represents a fully automatic pacemakerwhich is capable of sensing and pacing in both the atrium and theventricle, and is also capable of adjusting the pacing rate based on oneor more physiological factors, such as the patient's activity level. Itis commonly accepted that the DDDR pacemaker is superior in that it canmaintain AV synchrony while providing bradycardia (slow heart beat)support. It is also generally more expensive than other, simpler typesof pacemakers. A description of DDDR pacing is included in thisdiscloser as a state of the art.

In general, DDDR pacing has four functional states: (1) P-wave sensing,ventricular pacing (PV); (2) atrial pacing, ventricular pacing (AV); (3)P-wave sensing, R-wave sensing (PR); and (4) atrial pacing, R-wavesensing (AR).

It is accepted as important and advantageous, for the patient withcomplete or partial heart block, that the PV state of the DDDR pacemakertracks the atrial rate, which is set by the heart's SA node, and thenpaces in the ventricle at a rate that follows this atrial rate. It isadvertised that because the rate set by the SA node represents the rateat which the heart should beat in order to meet the physiologic demandsof the body (at least for a heart having a properly functioning SA node)the rate maintained in the ventricle by such a pacemaker is trulyphysiologic.

In some instances, a given patient may develop dangerously fast atrialrhythms, which result from a pathologic arrhythmia such as apathological tachycardia, fibrillation or flutter. In these cases, aDDDR pacemaker may pace the ventricle in response to the sensed atrialarrhythmia up to a programmed maximum tracking rate (MTR). The MTRdefines the upper limit for the ventricular rate when the pacemaker istracking the intrinsic atrial rate. As a result, the MTR sets the limitabove which the ventricles cannot be paced, regardless of the intrinsicatrial rate. Thus, the purpose of the MTR is to prevent rapidventricular stimulation, which could occur if the intrinsic atrial ratebecomes very high and the pacemaker attempts to track atrial activitywith 1:1 AV synchrony.

When the intrinsic atrial rate exceeds the MTR the pacemaker mayinitiate one or more upper atrial rate response functions—such asautomatically switching the pacemaker's mode of operation from an atrialtracking mode to a non-atrial rate tracking mode.

The heart's natural response to a very high atrial rate involves anatural phenomenon known as “blocking”—where the AV node attempts tomaintain a form of AV synchrony by “dropping out” occasional ventricularbeats when the high atrial rate exceeds a certain natural thresholdi.e., the refractory period of the heart tissue. The blocking phenomenonis often expressed as a ratio of the atrial beats to the ventricularbeats (e.g. 6:5, 4:3, etc.). Of particular importance is a 2:1 blockcondition where there are two atrial beats for every one ventricularbeat. The 2:1 block condition is a natural response to a very highatrial rate, during which full ventricular rate synchronization (i.e. ata 1:1 ratio) would be dangerous to the patient.

Some known pacemakers emulate this 2:1 condition, by tracking P-waves upto the device's programmed total refractory period (TARP) of the heart.That is, P-waves which fall in the total refractory period are nottracked, and the device is said to have a “2:1 response mode”. Duringthe 2:1 block response mode, the ventricles are paced at a lower ratethan the natural atrial rate, because P-waves occurring soon afterventricular events are ignored for the purposes of calculating theventricular pacing rate. As a result, the 2:1 block response modeprevents the pacemaker from pacing the ventricles at a tachycardia rate.

The 2:1 block response mode is an effective response for dealing withshort incidences of high atrial rates and in preventing occurrence of apacemaker mediated tachycardia resulting from retrograde P-waves.However, the 2:1 block response mode may become uncomfortable for thepatient if it is maintained for an extended period of time due toprogrammed long atrial refractory periods, because the pacing rate willbe ½ of the required physiologic rate.

Many more advanced pacemaker operation modes have been described andsometimes implemented. Some of these modes included sensing abnormallyhigh atrial rates and prevented them from causing rapid ventricularrates. Common to prior pacing no attempt has been made to induce a rapid(faster than normal) atrial rate by pacing or to pace atria at ratehigher than ventricles.

Natriuretic Peptides (ANP and BNP)

Atrial natriuretic peptide (ANP) is a hormone that is released frommyocardial cells in the atria and in some cases the ventricles inresponse to volume expansion and increased wall stress. Brainnatriuretic peptide (BNP) is a natriuretic hormone that is similar toANP. It was initially identified in the brain but is also present in theheart, particularly the ventricles.

The release of both ANP and BNP is increased in heart failure (CHF), asventricular cells are recruited to secrete both ANP and BNP in responseto the high ventricular filling pressures. The plasma concentrations ofboth hormones are increased in patients with asymptomatic andsymptomatic left ventricular dysfunction, permitting their use indiagnosis. A Johnson and Johnson Company Scios sells popular intravenous(IV) medication Natrecor (nesiritide), a recombinant form of theendogenous human peptide for the treatment of decompensated CHF. Theadvent of Natrecor marked an important evolution in the understandingand treatment of acute heart failure.

Both ANP and BNP have diuretic, natriuretic, and hypotensive effects.They also inhibit the renin-angiotensin system, endothelin secretion,and systemic and renal sympathetic activity. Among patients with CHF,increased secretion of ANP and BNP may partially counteract the effectsof norepinephrine, endothelin, and angiotensin II, limiting the degreeof vasoconstriction and sodium retention. BNP may also protect againstcollagen accumulation and the pathologic remodeling that contributes toprogressive CHF.

SUMMARY

Increasing levels of ANP and/or BNP in blood would benefit heart failurepatients. Unfortunately ANP and BNP cannot be taken as an oralmedication since it is a peptide and will be destroyed in the patient'sdigestive system. BNP is currently available as an IV injectablemedication. This limits its use to hospitals and special therapycenters. Many patients would benefit from the increased blood levels ofANP and BNP if the therapy did not require such professional settingsand was a part of their normal life.

There is a desire to cause a therapeutic increase of blood plasma ANPand BNP via an increased endogenous release of ANP and BNP from theatria of the patient's heart. Atrial release is mediated via increase ofatrial wall stress. The embodiments disclosed here include among others:the mechanical distension of the atria or atrial appendage, rapid pacingof the atria or subthreshold electric stimulation of atria.

Increased heart rates, seen with supraventricular tachycardia (SVT), areclinically associated with polyuria, or increased urine output. Thestart of the polyuria is coincident with the start of the tachycardiaand finishes with the end of the rapid rate. This observation wasconfirmed in humans by pacing them at high rates, which caused anincrease in ANP secretion within the first 30 minutes of pacing.

Electric Stimulation of the Heart

One embodiment disclosed here uses a modified implanted electroniccardiac pacemaker to increase ANP and BNP secretion by pacing the rightatrium of the patient at an appropriately high rate. At the same time itgenerally is not desired to substantially increase the ventricularcontraction rate of HF patients. Ventricular ejection at a ratesubstantially above normal may result in the insufficient time for theheart to relax and to refill with blood between the contractions.

Current cardiac pacemakers with the capability of pacing both the atriumand the ventricle stimulate the heart chambers in a “1:1” ratio, that isno more than one ventricular stimulus per atrial stimulus and viceversa. Few normal people, and certainly no patient with CHF, cantolerate high ventricular rates without hemodynamic compromise fromdecreased filling. This is one of the reasons many previous therapieshave chosen to try to slow heart rate in CHF and why beta-blockers orother negative chrontropic agents (drugs that slow down the heart rate)are preferred in the clinical treatment of CHF. For the purpose of thisinvention it would be desirable to have a device where the atrium couldbe stimulated at a high rate to cause release of ANP/BNP but withoutcausing clinically unacceptably high ventricular rates. For example,atrial rates could range from 120 to 240 bpm with ventricular rates inthe range of 50 to 110 per minute during pacing intended to releaseendogenous ANP/BNP. These rates would return to the normal ranges andatrial:ventricular stimulation ratio (i.e., 1:1) pacing as is incurrently clinically available pacemakers when the therapy isinterrupted or stopped.

In the described embodiment patients have either a naturalatrioventricular block (AV block) or have an AV block induced by hearttissue ablation or some other appropriate procedure. For example inpatients with a so-called third-degree AV block (complete AV block, noAV conduction), no atrial impulses reach the ventricles, and ventricularrhythm is maintained by a subsidiary natural pacemaker. Since subsidiarypacemakers must be below the level of block, their location is in partdetermined by the site of block. In third-degree AV nodal block, theventricular rhythm is usually maintained by pacemakers in the AVjunction with resultant narrow QRS complexes. In third-degree AV blocklocalized to the bundle branches, ventricular rhythm is maintained by apacemaker in the Purkinje fibers, with resultant wide QRS complexes. Thejunctional pacemaker rate is usually faster (40-80 beats/min) comparedwith the peripheral Purkinje network (20-40 beats/min). In such patientsa dual chamber pacemaker can be used to pace atria at a rate much higherthan the ventricles without the risk of patient developing dangerousventricular tachycardia (rapid heart beat). An atrioventricular (AV)node ablation is a known medical procedure that destroys a part of theheart's normal electrical system. The combination of pacing and AV nodeablation is sometimes used clinically in patients with chronic atrialfibrillation and rapid ventricular response that poorly respond to drugtherapy.

This is accomplished by cauterizing the AV node, which is locatedbetween the upper heart chamber (atria) and the lower heart chambers(ventricles). Once the AV node is cauterized, none or few impulses fromthe atria will be able to reach the ventricles. Currently an AV nodeablation is performed when the patient's rhythm disturbance (arrhythmia)originates in the atria and cannot be controlled adequately. A permanentpacemaker is installed afterwards, to keep the heart beating at a normalpace. The pacemaker lead is connected directly to a ventricle.

Electronic pacemakers are currently used to replace or supplement thenatural pacing nodes of the heart by applying electric excitory signalsto the heart muscle to cause contraction and blood pumping cycle.Pacemakers are used in patients with diseased nodes (slow heart beat)and defective (blocked) conduction pathways. Bi-ventricular pacemakerspace both ventricles of the heart to restore synchrony between theventricles.

Generally, the conventional wisdom of all pacing therapies for the heartdisease is as follows. A human heart consists of four chambers—two atriaand two ventricles. In order for the heart to efficiently perform itsfunction as a pump, the atrial muscles and ventricular muscles shouldcontract in a proper sequence and in a timed relationship, as they do ina healthy heart. Therefore electronic pacemakers are used to restore thenormal heartbeat or to restore synchrony between different chambers ofthe heart.

The inventors broke away from this tradition and proposed acounterintuitive approach to heart pacing. In the invention a pacemakeris counter intuitively used dissynchronously to generate differentatrial and ventricular contraction rates. Specifically a higher rate ofatrial contractions than ventricular contractions is generated. It isunderstood that this may result in suboptimal performance of the heart.Inventors propose that this disadvantage will be offset by the benefitof the increased ANP-BNP secretion by the heart atria in heart failurepatients.

Mechanical Stimulation

There is a desire to cause a therapeutic increase of blood plasma ANPand BNP via an increased endogenous release of ANP and BNP from theatria of the patient's heart. Atrial release is mediated via increase ofatrial wall stress. The embodiments disclosed herein include amongothers: the mechanical distension of the atria or atrial appendage,rapid pacing of the atria or subthreshold electric stimulation of atria.

One embodiment uses an implantable expandable device (such as aninflatable balloon) placed in an atrial appendage of the heart to causea therapeutic increase of blood plasma ANP and BNP via an increasedendogenous release of ANP and BNP in response to the artificiallyinduced changes of the atrial wall stress. The wall stress is caused byperiodic inflation of the balloon to the size that exceeds normal sizeof the appendage therefore distending its walls.

It is know in the field of cardiology that stretching or otherwisestressing tissue in the walls of the atria of the heart initiates therelease of endogenous ANP-BNP. No practical therapy or medical deviceresulted from this knowledge for the lack of a safe and simple methodand a technology enabling such release repeatedly over clinicallyrelevant duration of time.

The right atrial appendage (RAA) or the right auricle of the heart isthe appendicular portion of the right atrium that externally originatesfrom the terminal groove. In man, the RAA has a characteristictriangular “pocket” shape and resides inside the pericardial sac on topof the anterior (frontal) surface of the heart. The right atrialappendage is lined internally by pectinate muscles that originate fromthe terminal crest. The function of the RAA is unclear and its removalor isolation by surgery is not known or expected to have serious adverseeffects on the patient.

An implantable or implanted device (commonly termed an “implant”) is anartificial device fully enclosed in the patient's body. It issignificant that implants allow the natural skin of the patient to serveas a barrier against infection. Relevant to this invention an implantcan include, for example, an inflatable balloon, a complexelectromechanical pump, a catheter and/or an infusion port. Implantationcan be achieved by open surgery, minimally invasive surgery or atranscatheter intervention, whether extravascular, intravascular orcombination of any of the above. During the implantation procedure, asurgical instrument or catheter is used to cross the skin, penetratinginto the patient's body. The implant is positioned at the desired siteand the pathway used to access the site is closed. The site heals andthe device is now fully implanted.

Cyclically stretching or otherwise stressing the atria of a patient canresult in benefits other or in addition to simple ANP and BNP release.Such benefits can include activation of neuron-hormonal mechanisms andadditional release of other hormones that can benefit patients with highblood pressure and heart failure. Of particular importance for theinvention are known physiologic pathways between the heart muscle, thebrain and the kidneys that can result in vasodilatation of blood vesselsand increased urine output in response to atrial stretch. Fulldescription of these interactions goes beyond the scope of thisinvention and can be obtained from literature on cardio-renalphysiology.

Stretching or otherwise stressing the atria of a patient can be achievedin many different ways, for example, by pulling on the atrial appendage,pulling on the atria or on the junctions between the great vessels andthe heart atria.

The choice of an inflatable balloon implanted in the right atrialappendage was justified by its simplicity but other controllablyexpandable medical devices could potentially serve the same purpose.

The right atrial appendage is not the only part of the heart that, whenstressed by stimulation, can release beneficial hormones. The choice ofthe site was justified by the easy surgical and vascular access and lowrisk of blood clotting. It is understood that similar manipulation of,for example, left atrial appendage, can achieve similar results.

SUMMARY OF THE DRAWINGS

A preferred embodiment and best mode of the invention is illustrated inthe attached drawings that are described as follows:

FIG. 1 illustrates the electric excitory pathways and chambers of ahuman heart.

FIG. 2 illustrates the embodiment of the invention with a two leadpacing system.

FIG. 3 illustrates one sequence of natural and induced stimulationpulses.

FIG. 4 illustrates intermittent asynchronous pacing.

FIG. 5 illustrates an inflatable balloon in right atrial appendage ofthe heart.

FIG. 6 illustrates the embodiment of the invention with a two leadpacing system.

DETAILED DESCRIPTION

FIG. 1 shows a normal heart. Electrical pulses in the heart arecontrolled by special groups of cells called nodes. The rhythm of theheart is normally determined by a pacemaker site called the sinoatrial(SA) node 107 located in the posterior wall of the right atrium 102 nearthe superior vena cava (SVC) 101. The SA node consists of specializedcells that undergo spontaneous generation of action potentials at a rateof 100-110 action potentials (“beats”) per minute. This intrinsic rhythmis strongly influenced by autonomic nerves, with the vagus nerve beingdominant over sympathetic influences at rest. This “vagal tone” bringsthe resting heart rate down to 60-80 beats/minute in a healthy person.Sinus rates below this range are termed sinus bradycardia and sinusrates above this range are termed sinus tachycardia.

The sinus rhythm normally controls both atrial and ventricular rhythm.Action potentials generated by the SA 107 node spread throughout theatria, depolarizing this tissue and causing right atrial 102 and leftatrial 106 contraction. The impulse then travels into the ventricles viathe atrioventricular node (AV node) 108. Specialized conduction pathwaysthat follow the ventricular septum 104 within the ventricles rapidlyconduct the wave of depolarization throughout the right 103 and left 105ventricles to elicit the ventricular contraction. Therefore, normalcardiac rhythm is controlled by the pacemaker activity of the SA nodeand the delay in the AV node. Abnormal cardiac rhythms may occur whenthe SA node fails to function normally, when other pacemaker sites(e.g., ectopic pacemakers) trigger depolarization, or when normalconduction pathways are not followed.

FIG. 2 shows a heart treated with one embodiment of the invention. Pulsegenerator (pacemaker) 201 is implanted in a tissue pocket in thepatient's chest under the skin. In this embodiment the generator 201 isconnected to the heart muscle by two electrode leads. The ventricularlead 202 is in contact with the excitable heart tissue of the rightventricle 103. The atrial lead 203 is in contact with the excitableheart tissue of the right atrium 102. It is understood that thepacemaker can have more leads such as a third lead to pace the leftventricle 105. It is expected that in future cardiac pacemakers willhave even more leads connecting them to various parts of the anatomy.

Leads 203 and 202 can combine sensing and pacing electrodes as known andcommon in the field. The atrial lead 203 can therefore sense the naturalintrinsic contractions of the atria before they occur and communicatethem to the generator 201. The generator is equipped with theprogrammable logic that enables it to sense signals, process theinformation, execute algorithms and send out electric signals to theleads.

In this embodiment the natural conduction path between the SA node 107and the AV node 108 is blocked. The patient may already have a naturalcomplete AV block. In this case no intervention is needed. If thepatient has functional electric pathways from atria to ventricles, thepatient's AV node can be disabled (blocked) by tissue ablation. It isunderstood that many irreversible and reversible methods of selectivelyblocking conduction in the heart are known. These include treatment withchemical agents and blocking with subthreshold electric stimulation(non-excitatory stimulation that does not cause muscle fibers tocontract). Ablation of the AV node is used as an example since it iswidely accepted and easily performed using RF energy catheters. Otherdevices that use cold, laser and ultrasound energy to perform ablationare also known.

FIG. 3 illustrates one possible embodiment of the invention with asequence of stimulation pulses. Pulses are simplified and presented asrectangular blocks spaced in time as represented by the X-axis.

Trace 301 illustrates the natural or intrinsic rate generated by the SAnode of the heart. The SA node generates pulses 304, 305, 306 and 307.These pulses can be sensed by the atrial lead 203.

In response to the sensing of intrinsic atrial pulses, the pulsegenerator 201 generates a series of pulses represented by the trace 302.Pulses are conducted to the atria by the atrial lead 203. Devicegenerated atrial stimulation pulses 311, 313, 315 and 317 are insynchrony with the SA node pulses 304, 305, 306 and 307. They representthe intrinsic heart rate. The generator 201 (based on an embeddedalgorithm) also generates extra atrial pulses 312, 314 and 316. Togethersynchronous pulses 311, 313, 315, 317 and asynchronous pulses 312, 314,316 determine the atrial rate of the heart.

Trace 303 represents ventricular stimulation pulses 321, 322, 323 and324 conducted to the ventricle of the heart by the ventricular lead 202.The AV node of the heart in this embodiment is blocked. Therefore theventricular stimulation is generated by the generator 201 based on anembedded algorithm. To ensure better performance of the heartventricular pulses 321, 322, 323 and 324 are synchronized to thesynchronous atrial pulses 311, 313, 315 and 317 with a short delay 308determined by the embedded algorithm that simulates the natural delay ofthe AV node conduction.

The algorithm illustrated by the FIG. 3 can be described as a followingsequence:

a. sensing an intrinsic SA node pulse (P-wave),

b. generating a synchronous atrial pacing pulse,

c. calculating the intrinsic atrial rate based on previous SA node pulseintervals,

d. generating synchronous ventricular pacing signal delayed from thesynchronous atrial pacing signal at the ventricular rate equal to theintrinsic SA node excitation rate (sinus rhythm),

e. calculating the desired increased atrial rate, such as for example, a2:1 (A:V) rate,

f. generating asynchronous atrial pacing signal based on the calculatedincreased atrial rate, and

g. waiting for the next intrinsic SA node pulse (P-wave).

It is understood that this example of an algorithm is an illustrationand many other embodiments of the invention can be proposed. It can beenvisioned that more than 2:1 (atrial:ventricular) rate can be toleratedby the patient or that less than 2:1 rate is desired such asaccelerating every second atrial beat.

It may be not essential to preserve the natural sinus rhythm (from theSA node). In some patients it may be desired for the algorithm to takeover the heart rate and force all the atrial contraction. Pacingmodalities that do not rely on the SA node to generate the heart rateare known and used to treat bradycardia. The SA node of a patient can beablated similar to the AV node and the embedded pacemaker algorithm willpace the atria. Alternatively, atria may be paced if the natural SA nodepulse is not sensed within the expected time from the last ventricularcontraction. Various activity sensors such as accelerometers can be usedto accelerate the heart rate as needed.

FIG. 4 illustrates intermittent application of the proposed therapy. Itis possible that some patients will not need or will not be able totolerate continuous asynchronous A-V (atria-ventricular) pacing. In suchpatient period of normal (synchronous) pacing 401 is followed by theperiod of asynchronous (accelerated atrial) pacing 402 followed again bythe period of synchronous pacing 403. The ventricular pacing rate 405 inthis example stays the same. Switching between rates can be based ontiming, patient's activity or physiologic feedbacks. For example, thepattern of therapy using electrical stimuli to generate high atrialrates can be intermittent of varying duration of accelerated atrialpacing in intervals of 10-minute durations occurring, for example, 3times per day.

Commonly, in comparison to previous devices, this embodiment of theinvention purposefully creates ratios of atrial to ventricularcontraction higher than 1:1, such as for example in the range of 1:1 to4:1. In addition, any previous device that allowed more than a 1:1 ratioof contraction based this relationship on sensing native atrialdepolarization and deferring generation of a ventricular pacing stimulus(skipping premature ventricular beats). In contrast, in the illustratedembodiment, the higher than 1:1 rate is intentionally and controllablyinitiated by the implantable generator. As a result the atrial rate isincreased to a rate which causes the release of sufficient endogenousnaturetic hormone to result in a therapeutically beneficial increase inblood plasma levels of the hormones or increased levels in any othervascular or non-vascular space in which these hormones a found.

It is desirable to cause a therapeutic increase of blood plasma ANP andBNP via an increased endogenous release of ANP and BNP from the atria ofthe patient's heart. Atrial release is mediated via increase of atrialwall stress. The best embodiment of the invention known to the inventorsat the time of the invention is rapid pacing of the atria that isexpected to increase the rate of contractions of the atria and releaseANP and BNP. The invention has been described in connection with thebest mode now known to the applicant inventors. The invention is not tobe limited to the disclosed embodiment. Rather, the invention covers allof various modifications and equivalent arrangements included within thespirit and scope of the appended claims.

FIG. 1 shows a normal heart. Electrical pulses in the heart arecontrolled by special groups of cells called nodes. The rhythm of theheart is normally determined by a pacemaker site called the sinoatrial(SA) node 107 located in the posterior wall of the right atrium 102 nearthe superior vena cava (SVC) 101. The SA node consists of specializedcells that undergo spontaneous generation of action potentials at a rateof 100-110 action potentials (“beats”) per minute. This intrinsic rhythmis strongly influenced by autonomic nerves, with the vagus nerve beingdominant over sympathetic influences at rest. This “vagal tone” bringsthe resting heart rate down to 60-80 beats/minute in a healthy person.Sinus rates below this range are termed sinus bradycardia and sinusrates above this range are termed sinus tachycardia.

FIG. 5 shows a human heart 500 treated with one embodiment of theinvention. Heart is shown inside the pericardial sac 509 that is cutopen. Heart has a right atrium (RA) 501, a superior vena cava (SVC) 503and an inferior vena cava (IVC) 504. The purpose of the embodiment is tostretch the walls of the right atrial appendage (RAA) 502. The RAAstretching results in the ANP and BNP increase and benefits to patientswith heart disease and such as heart failure (CHF) or hypertension. RAAstretching is achieved by periodically expanding the inflatable balloon505 inside the RAA. The balloon 505 is mounted on the tip of thecatheter 507. The catheter 507 is connected with an inflation device(See FIG. 2) that can be implanted elsewhere in the body. Both IVC 504and SVC 503 can be used to advance the catheter into the RA 501 andfurther into RAA 502. Methods of placing and securing similar devices inthe RA of the heart are well known in the field of electrophysiology andcardiology and routinely used to place pacemaker electrode leads inpatients. In the illustrated embodiment the balloon 505 is advanced deepinto the apex 508 of the RAA 502 and secured there with an anchor 506.The purpose of advancing the balloon into the apex and securing it thereis to reduce the probability of clotting of the blood in the stagnantblood flow zones formed by the balloon and to prevent the balloon fromfloating out of the RAA. The anchor 506 can be a barb or a screw similarto ones used to anchor pacemaker leads in the heart. The surface of theballoon can be made of a material or is externally coated with amaterial such as porous ePTFE that encourages in-growth of tissue. It isknown that, when a tissue implant is porous with pore entry diameterslarger than approximately 20 to 500 microns, tissue grows into thesepores. This phenomenon appears desirable in many medical deviceapplications because it makes an implant one with the implanted organand in theory it allows tissue ingrowth into the implant and reducescapsular contraction. This way in several weeks after the implantationthe balloon 505 will be fused with the inner walls of the RAA 502 tofurther prevent clotting or dislodgement of the balloon.

FIG. 6 shows a patient 600 treated with one embodiment of the invention.Fluid pump 602 is implanted in a tissue pocket in the patient's bodyunder the skin. In this embodiment the pump 602 is connected to theballoon 505 placed in the RAA 508 by the fluid filled catheter 507. Itis understood that the pump 602 can be implanted elsewhere in the body,that the catheter 507 can follow a different vascular route and that theballoon 505 can be placed in different locations in the RA or LeftAtrium (LA) of the heart. These modifications to the embodiment will notchange the substance of the invention.

An implantable pump 602 is an implantable device that is inserted underthe patient's skin and can be refilled using a transdermal needle 602access. An implantable pump may be attached to a separate catheter 507that delivers fluid to and from the expandable balloon 505. Depending onthe desired treatment modality, a preferred implantable pump can beprogrammable, patient controlled or physician controlled. The pump canbe mechanical (activated by finger pressure) or electro-mechanical usingmotors or solenoid pistons to generate flow and pressure.

The catheter 504 can be introduced into the RAA space underfluoroscopic, MRI or CT guidance without major surgery. The procedure isperformed using an access point in a femoral vein 601 in the groin ofthe patient 600 using tools and techniques commonly used ininterventional cardiology and radiology. One end of the catheter can beleft outside of the body for the test period that requires only a shortduration. Later, if the atrial stretching therapy is clinicallysuccessful, an implanted pump or a simple implanted subcutaneousinfusion port such as a commercially available Port-A-Cath™ device canbe connected to the already implanted catheter for repeat infusions andwithdrawals of fluid into and from the balloon 505. Alternatively theballoon can be inserted into the RAA surgically by piercing the wall ofthe RAA 508 from the outside. The actual method of inserting andsecuring the balloon in the RAA will not change the substance of theinvention. General approach in implantable devices is that less invasivemethods of implantation are preferred in most cases but tend to be moredemanding.

In the illustrated embodiment the pump 602 in implanted in a pocketunder the patient's skin. All the mechanisms of the pump are enclosed ina titanium or polymer case. Fluid is stored in the internal reservoir(not shown). To refill the pump or to add or remove fluid, a needle 602can be used to puncture the patient's skin and the pump reservoir septum(Not shown). The catheter 504 is in bidirectional fluid communicationwith the pump 602 and the balloon 505. All the fundamental elementsdescribed above are known to the developers of implantable drug pumps.An example of an implantable drug infusion device is the MiniMed 6007™implantable insulin pump system for treatment of diabetes or theSynchroMed™ Infusion System used to control chronic pain, bothmanufactured by Medtronic Inc.

The proposed embodiment is different from the existing implantable druginfusion pumps in the following significant way. In existing druginfusion pumps fluid is infused in one direction always from theimplanted pump reservoir into the body. In this invention the fluid isbidirectionally moved (shuttled) inside a closed system in bothdirections between the implanted pump and the implanted balloon.Historically implantable infusion devices have been used forintravenous, intraarterial, intrathecal, intraperitoneal, intraspinaland epidural drug delivery but not to control inflation and deflation ofimplanted balloons.

For the purpose of an estimate the balloon 105 can have a diameter of 1cm when the RAA is not stretched and the diameter of 2 to 3 cm when theRAA is stretched. The balloon is 3 cm long. This implies shuttling ofapproximately 5 to 20 ml of incompressible fluid between the pumpreservoir and the balloon. This requirement is within reasonable rangefor a fully implanted pump of the described type. The MedtronicSynchroMed pump for example has a miniature peristaltic pump mechanismthat can be modified to operate bidirectionally and generate necessarypressures. It also has an internal fluid reservoir of 30 ml. The fluidcan be a sterile, biocompatible fluid that will not harm the patient ifit leaks out such as saline, glycerin or medical grade oil. The balloon105 can be made of silicone, nylon or other strong medical plasticsuited for multiple cycle inflation and deflation. Methods and materialsfor manufacturing of durable, implantable balloons exist and have beensuccessfully implemented in many medical device applications.

The therapy may include the following steps:

Identifying a patient that will benefit from elevated levels of ANP andBNP likely from the group with heart failure, fluid retention orhypertension

Implanting an expandable device in an atrial appendage of the patientsheart

Periodically expanding and contracting the device to temporarily stretchthe walls of the atrium to achieve therapeutically significant increaseof blood hormones.

The exact regiment of stretching and contracting the atrial wall islikely to be individual for each patient. For example a regiment can beproposed where the balloon is inflated for several minutes followed byseveral minutes of rest. These cycles will be repeated for several hoursseveral times each day. In heart failure patients with fluid retentionthe objective of therapy will be to achieve minimum additional urineoutput of 250 ml per day and preferably 500 ml per day. The high end ofthe therapeutic range may be 1,000 additional ml of urine per day. Thisadditional urine output is likely to improve patient's condition, allowmore exercise and prevent hospital admissions from fluid overload. It islikely that the device will require a pump component that is remotelyprogrammable so that the therapy parameters can be adjusted usingwireless communication.

The adjustable programmable parameters may include:

Volume of Balloon Expansion

Duty cycle and frequency of inflation cycles in each therapy session

Number and time of therapy sessions hourly, daily or weekly

The methodology of programming an implantable pump is not different fromprogramming a common heart pacemaker.

The invention has been described in connection with the best mode nowknown to the applicant inventors.

The invention is not to be limited to the disclosed embodiment. Rather,the invention covers all of various modifications and equivalentarrangements included within the spirit and scope of the appendedclaims.

What is claimed is:
 1. A method for treating a patient comprising:determining that the patient is suffering from a condition comprising atleast one of hypertension, excessive fluid retention, and excessivesodium retention; treating the condition by stressing a wall of at leastone atrium of the heart beyond a natural stress condition of the wall,such that the stressed wall secretes a hormone at an elevated levelabove a natural secretion level occurring naturally when the wall of theat least one atrium is not stressed by the stressing; and achieving abeneficial therapeutic effect in the patient by the hormone secreted atthe elevated level, wherein the beneficial therapeutic effect includes areduction in blood pressure.
 2. The method of claim 1, wherein stressingthe wall of the at least one atrium comprises expanding and contractingan expandable device implanted in an atrial appendage of the heart totemporarily stretch the wall of the at least one atrium.
 3. The methodof claim 2, wherein the expandable device comprises an inflatableballoon.
 4. The method of claim 2, wherein expanding and contracting theexpandable device comprises using an implanted pump connected to theexpandable device to bidirectionally shuttle fluid in a closed systembetween the expandable device and the implanted pump.
 5. The method ofclaim 2, further comprising anchoring the expandable device in an apexof a right atrial appendage of the heart.
 6. The method of claim 1,wherein stressing the wall of the at least one atrium of the heartcomprises stretching the wall and then restoring the wall to asubstantially pre-stretched condition.
 7. The method of claim 1, whereinstressing the wall of the at least one atrium comprises pacing the atleast one atrium.
 8. The method of claim 7, wherein pacing the at leastone atrium is performed at an accelerated rate.
 9. The method of claim1, wherein stressing the wall of the at least one atrium comprisesasynchronously pacing the at least one atrium and at least one ventricleof the heart such that a pacing rate of the at least one atrium exceedsa pacing rate of the at least one ventricle.
 10. The method of claim 1,wherein stressing the wall of the at least one atrium comprisesmechanical distension of a right atrial appendage of the heart.
 11. Themethod of claim 1, wherein stressing the wall of the at least one atriumcomprises pacing of the at least one atrium that results in increasedcontractions of the at least one atrium.
 12. The method of claim 1,wherein stressing the wall of the at least one atrium of the heartcomprises pacing of the at least on atrium that stresses the wall of theat least one atrium beyond the natural stress condition.
 13. The methodof claim 1, wherein the beneficial therapeutic effect includes at leastone of: limiting a degree of vasoconstriction, limiting a degree ofsodium retention, increasing urine output, inhibiting arenin-angiotensin system, inhibiting endothelin secretion, inhibitingsystemic and renal sympathetic activity, and counteracting effects of atleast one of norepinephrine, endothelin, and angiotensin II.
 14. Aprogrammable implantable pacemaker connectable to at least oneelectrically conductive lead for connecting to a heart of a patient, thepacemaker being programmed to pace the heart of the patient to stress awall of at least one atrium of the heart, such that, with the patientsuffering from a condition comprising at least one of hypertension,excessive fluid retention, and excessive sodium retention: the stressedwall secretes a hormone at an elevated level above a natural secretionlevel occurring naturally when the heart is not stressed by the pacing,and a beneficial therapeutic effect is achieved in the patient by thehormone secreted at the elevated level, wherein the beneficialtherapeutic effect includes a reduction in blood pressure.
 15. Thepacemaker of claim 14, wherein the pacemaker is programmed to stress thewall of the at least one atrium of the heart beyond a natural stresscondition of the wall.
 16. The pacemaker of claim 14, wherein thepacemaker is programmed to asynchronously pace the at least one atriumand at least one ventricle of the heart such that a pacing rate of theat least one atrium exceeds a pacing rate of the at least one ventricle.17. The pacemaker of claim 14, wherein the pacemaker is programmed topace the at least one atrium so as to cause increased contractions ofthe at least one atrium.
 18. The pacemaker of claim 14, wherein thepacemaker is programmed to alternate pacing of the heart between a firstpacing period that asynchronously paces the at least one atrium and asecond pacing period that paces the at least one atrium normally. 19.The pacemaker of claim 14, wherein the pacemaker is programmed toalternate pacing of the heart between a first asynchronous pacing periodand a second normal pacing period that synchronously paces the at leastone atrium and at least one ventricle of the heart.
 20. The pacemaker ofclaim 14, further comprising one or more electrically conductive leadsconnected to the pacemaker.
 21. The pacemaker of claim 14, wherein thebeneficial therapeutic effect includes at least one of: limiting adegree of vasoconstriction, limiting a degree of sodium retention,increasing urine output, inhibiting a renin-angiotensin system,inhibiting endothelin secretion, inhibiting systemic and renalsympathetic activity, and counteracting effects of at least one ofnorepinephrine, endothelin, and angiotensin II.
 22. A method fortreating a patient comprising: determining that the patient is sufferingfrom a condition comprising at least one of hypertension, excessivefluid retention, and excessive sodium retention; treating the conditionby pacing a heart of the patient to stress a wall of at least one atriumof the heart, such that the stressed wall secretes a hormone at anelevated level above a natural secretion level occurring naturally whenthe heart is not stressed by the pacing; and achieving a beneficialtherapeutic effect in the patient by the hormone secreted at theelevated level, wherein the beneficial therapeutic effect includes areduction in blood pressure.
 23. The method of claim 22, wherein pacingthe heart to stress the wall of the at least one atrium comprisesalternating between a first pacing period that asynchronously paces theat least one atrium and a second pacing period that paces the at leastone atrium normally.
 24. The method of claim 22, wherein pacing theheart to stress the wall of the at least one atrium comprises a firstasynchronous pacing period, and wherein the method further comprisesalternating between the first asynchronous pacing period and a secondnormal pacing period that synchronously paces the at least one atriumand at least one ventricle of the heart.
 25. The method of claim 24,wherein the first asynchronous pacing period comprises acceleratedatrial pacing.
 26. The method of claim 24, wherein pacing the heartcomprises applying the first asynchronous pacing period three times perday.
 27. The method of claim 22, wherein pacing the heart comprisespacing at least one ventricle of the heart.
 28. The method of claim 22,wherein pacing the heart comprises pacing a ventricle of the heart at afirst rate and pacing the at least one atrium at a second rate that isfaster than the first rate.
 29. The method of claim 28, wherein thefirst rate is within a range of about 50 to about 110 bpm and the secondrate is within a range of about 120 to about 240 bpm.
 30. The method ofclaim 22, wherein pacing the heart comprises pacing the heart tocyclically contract the at least one atrium, stress the wall of the atleast one atrium, and restore the wall of the at least one atrium to asubstantially pre-stressed condition.
 31. The method of claim 22,wherein pacing the heart produces extra contractions of the at least oneatrium.
 32. The method of claim 22, wherein the beneficial therapeuticeffect includes at least one of: limiting a degree of vasoconstriction,limiting a degree of sodium retention, increasing urine output,inhibiting a renin-angiotensin system, inhibiting endothelin secretion,inhibiting systemic and renal sympathetic activity, and counteractingeffects of at least one of norepinephrine, endothelin, and angiotensinII.